Assessment of Etravirine Resistance in HIV-1-Infected Paediatric Patients using Population and Deep Sequencing: Final Results of the PIANO Study

Abstract

Background

We assessed etravirine resistance in treatment-experienced, HIV-1-infected children (n=41)/adolescents (n=60) who received twice-daily etravirine 5.2 mg/kg and a background regimen (boosted protease inhibitor plus nucleoside/nucleotide reverse transcriptase inhibitors, optional enfuvirtide/raltegravir) in a Phase II, open-label, multicentre trial (PIANO).

Methods

In addition to phenotypes, viral genotypes were assessed by population and deep sequencing (PS and DS) in virological failures (VFs; baseline and end point) and responders (baseline). Minority resistance-associated mutations (RAMs) were defined as those with frequencies above 1% and not detected with PS.

Results

By week 48, 41/101 (40.6%) patients experienced VF; 17/41 (41.5%) VFs and 22/54 (40.8%) responders had ≥1 baseline etravirine RAM by PS, mainly A98G, K101E, V106I and G190A. Baseline minority etravirine RAMs (n) were detected in 8/40 VFs (V90I [2], A98G [1], L100I [1], V106I [1], E138G [1] and Y181C [2]) and 5/38 responders (V90I [3], A98G [1], V106I [1] and E138G [1]). The most frequent emerging non-nucleoside reverse transcriptase inhibitor RAMs detected by PS (≥3 VFs; n) were the etravirine RAMs Y181C (8), V90I (3), L100I (3) and E138A (3). In 15 of 29 (51.7%) VFs with baseline DS/PS and end point PS data, ≥1 emerging etravirine RAM was detected by PS, which was not detected at baseline by DS in most cases (12/15 [80.0%]). In 10/26 (38.5%) VFs with baseline/end point DS data, ≥1 additional emerging minority etravirine RAM was detected.

Conclusions

Patterns of etravirine resistance in adults, adolescents and children experiencing VF are similar. The presence of minority etravirine RAMs at baseline was not consistently associated with treatment failure. ClinicalTrials.gov: NCT00665847.

References

Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Department of Health and Human Services. (Updated 5 March 2015. Accessed 2 July 2015.) Available from http://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv-guidelines/0/.

Cortez

K.J.

, Maldarelli

Clinical management of HIV drug resistance.

Viruses 2011; 3: 347–378.

Tang

M.W.

, Shafer

R.W.

HIV-1 antiretroviral resistance: scientific principles and clinical applications.

Drugs 2012; 72: e1–e25.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Duman Services. (Updated 8 April 2015. Accessed 2 July 2015.) Available from http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0.

de Mulder

, Yebra

, Navas

Trends in drug resistance prevalence in HIV-1-infected children in Madrid: 1993 to 2010 analysis.

Pediatr Infect Dis J 2012; 31: e213–e221.

Sigaloff

K.C.

, Calis

J.C.

, Geelen

S.P.

, van Vugt

, de Wit

T F.

HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: a systematic review.

Lancet Infect Dis 2011; 11: 769–779.

Puthanakit

, Jourdain

, Hongsiriwon

HIV-1 drug resistance mutations in children after failure of first-line nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

HIV Med 2010; 11: 565–572.

Etravirine EMA summary of product characteristics 2008. (Updated 22 May 2014. Accessed 2 July 2015.) Available from http://www.medicines.org.uk/emc/print-document?documentId=25606.

Etravirine US prescribing information 2008. (Updated August 2014. Accessed 2 July 2015) Available from http://www.intelence.com/shared/product/intelence/prescribing-information.pdf.

10.

Katlama

, Haubrich

, Lalezari

Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomised, controlled trials.

AIDS 2009; 23: 2289–2300.

11.

Katlama

, Clotet

, Mills

Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials.

Antivir Ther 2010; 15: 1045–1052.

12.

Lazzarin

, Campbell

, Clotet

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24 week results from a randomised, double-blind, placebo-controlled trial.

Lancet 2007; 370: 39–48.

13.

Madruga

J.V.

, Cahn

, Grinsztejn

Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24 week results from a randomised, double-blind, placebo-controlled trial.

Lancet 2007; 370: 29–38.

14.

Tudor-Williams

, Cahn

, Chokephaibulkit

Safety, efficacy and resistance analysis of etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week results from the phase II PIANO study.

HIV Med 2014; 15: 513–524.

15.

Königs

, Feiterna-Sperling

, Esposito

Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents.

AIDS 2012; 26: 447–455.

16.

Johnson

V.A.

, Clavez

, Günthard

H.F.

2011 update of the drug resistance mutations in HIV-1.

Top Antivir Med 2011; 19: 156–164.

17.

Tambuyzer

, Azijn

, Rimsky

L.T.

Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors.

Antivir Ther 2009; 14: 103–109.

18.

Tambuyzer

, Nijs

, Daems

, Picchio

, Vingerhoets

Effect of mutations at position E138 on HIV-1 reverse transcriptase on phenotypic susceptibility and virologic response to etravirine.

J Acquir Immune Defic Syndr 2011; 58: 18–22.

19.

Vingerhoets

, Tambuyzer

, Azijn

Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies.

AIDS 2010; 24: 503–514.

20.

Vingerhoets

, Nijs

, Tambuyzer

, Hoogstoel

, Anderson

, Picchio

Similar predictions of etravirine sensitivity regardless of genotypic testing method used: comparison of available scoring systems.

Antivir Ther 2012; 17: 1571–1579.

21.

Thys

, Van Hove

, Van Rossem

Assessing the use of Illumina technology for deep sequencing in virology application.

Antivir Ther 2012; 17 Suppl 1: A154.

22.

Bennett

Solexa Ltd.

Pharmacogenomics 2004; 5: 433–438.

23.

Tambuyzer

, Nijs

, Tomaka

, Picchio

, Vingerhoets

Baseline and emerging resistance to etravirine in HIV-1-infected children and adolescents: final results from the Phase II PIANO study.

Antivir Ther 2012; 17 Suppl 1: A58.

24.

Tambuyzer

, Vingerhoets

, Azijn

Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies.

AIDS Res Hum Retroviruses 2010; 26: 1197–1205.

25.

Phelps

B.R.

, Rakhmanina

Antiretroviral drugs in pediatric HIV-infected patients: pharmacokinetic and practical challenges.

Paediatr Drugs 2011; 13: 175–192.

26.

Funk

M.B.

, Notheis

, Schuster

Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children.

Eur J Med Res 2005; 10: 503–508.

27.

Luzuriaga

, McManus

, Mofenson

A trial of three antiretroviral regimens in HIV-1-infected children.

N Engl J Med 2004; 350: 2471–2480.

28.

Delaugerre

, Rohban

, Simon

Resistance profile and cross-resistance of HIV-1 among patients failing a non-nucleoside reverse transcriptase inhibitor-containing regimen.

J Med Virol 2001; 65: 445–448.

29.

Vingerhoets

, Azijn

, Fransen

TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments.

J Virol 2005; 79: 12773–12782.

30.

Johnson

J.A.

, Li

J.F.

, Wei

Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy.

PLoS Med 2008; 5: e158.

31.

Paredes

, Lalama

C.M.

, Ribaudo

H.J.

Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure.

J Infect Dis 2010; 201: 662–671.

32.

Rowley

C.F.

, Boutwell

C.L.

, Lee

E.J.

Ultrasensitive detection of minor drug-resistant variants for HIV after nevirapine exposure using allele-specific PCR: clinical significance.

AIDS Res Hum Retroviruses 2010; 26: 293–300.

33.

J.Z.

, Paredes

, Ribaudo

H.J.

Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis.

JAMA 2011; 305: 1327–1335.

34.

Goodman

D.D.

, Zhou

, Margot

N.A.

Low level of the K103N HIV-1 above a threshold is associated with virological failure in treatment-naive individuals undergoing efavirenz-containing therapy.

AIDS 2011; 25: 325–333.

35.

Gianella

, Delport

, Pacold

M.E.

Detection of minority resistance during early HIV-1 infection: natural variation and spurious detection rather than transmission and evolution of multiple viral variants.

J Virol 2011; 85: 8359–8367.

36.

Metzner

K.J.

, Rauch

, Braun

Prevalence of key resistance mutations K65R, K103N, and M184V as minority HIV-1 variants in chronically HIV-1 infected, treatment-naive patients.

J Clin Virol 2011; 50: 156–161.

37.

J.Z.

, Paredes

, Ribaudo

H.J.

Relationship between minority nonnucleoside reverse transcriptase inhibitor resistance mutations, adherence, and the risk of virologic failure.

AIDS 2012; 26: 185–192.

38.

Messiaen

, Verhofstede

, Vandenbroucke

Ultra-deep sequencing of HIV-1 reverse transcriptase before start of an NNRTI-based regimen in treatment-naive patients.

Virology 2012; 426: 7–11.

39.

Lehman

D.A.

, Wamalwa

D.C.

, McCoy

C.O.

Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment.

J Acquir Immune Defic Syndr 2012; 60: 225–233.

40.

Snedecor

S.J.

, Khachatryan

, Nedrow

The prevalence of transmitted resistance to first-generation non-nucleoside reverse transcriptase inhibitors and its potential economic impact in HIV-infected patients.

PLoS ONE 2013; 8: e72784.